SUMMARY Each year in the United States, trauma, radiation therapy to treat urological cancers, severe cases of spina bifida, and interstitial cystitis contribute to at least 14,000 bladder augmentation enterocystoplasty surgeries. Although it is the standard of care for patients with an end-stage pathologic bladder, enterocystoplasty causes many complications due to anatomical and physiological differences between bladder tissue and the bowel tissue used to augment the bladder?s capacity. Several strategies have been reported to replace enterocystoplasty and regenerate bladder tissue but these have failed clinically. Reasons for the failure include the common use of phylogenetically dissimilar pre-clinical animal models that do not accurately represent the human bladder or its disease condition, the use of inadequate materials to serve as scaffolds for cells to grow on and regenerate bladder tissue, the use of often diseased autologous bladder cells that have lost the capacity to regenerate functional bladder tissue, and an inability to continuously monitor the tissue regeneration process to identify potential problems at an early stage. As a result, there is currently no viable alternative to augmentation enterocystoplasty. Regenerative engineering is a convergence of advanced material science, stem cell science, physics, and clinical translation. The overall goal of this project is to drive the development of unprecedented regenerative engineering tools and technologies via the integration of stem cell science, advanced biomaterials, and bio-integrated electronics to enable the regeneration of functional bladder tissue and the non-invasive, real-time assessment thereof to better predict outcome. Toward this goal, we have demonstrated our ability to: a) regenerate vascularized and innervated bladder tissue in a rat bladder augmentation model using a combination of bone marrow (BM) mesenchymal stem cells (MSCs), hematopoietic stem/progenitor cells (HSPCs), and an antioxidant citrate-based biodegradable elastomer, b) demonstrated successful bladder reconstruction with autologous cell-seeded POC scaffolds at 6 months in baboon; c) measure rat bladder pressure and control its function via a bio-integrated electronic strain gauge and light-activated excitatory channels, d) integrate stretchable electronics into citrate-based elastomers, and e) achieve wireless transmission of real time physiological data obtained in vivo using bio-integrated electronics. Towards our goal, the specific aims of this proposal are to: 1) Design, fabricate, and characterize bio-integrated electronics that monitor and modulate the function of regenerating bladder tissue via telemetry, 2) Engineer and characterize Stretch Monitoring Advanced Regenerative Telemetric (SMART) scaffolds for bladder augmentation, and 3) Assess the safety and efficacy of bladder conformal stretchable electronics and SMART scaffolds in a baboon bladder augmentation model.